Developing rational combination therapeutic strategies for diffuse intrinsic pontine glioma
Abstract/Contents
- Abstract
- Diffuse intrinsic pontine glioma (DIPG), recently reclassified as diffuse midline glioma (DMG), H3K27M mutant, is a universally fatal disease. Despite decades of clinical efforts, radiotherapy remains the only transiently effective therapy. Currently, median survival remains 11 months with 90% of children dying within 2 years of diagnosis. In search of effective therapeutic strategies, we developed a method to generate patient-derived DMG cell cultures from early post-mortem tissue donations. Using these cultures, we performed systematic quantitative high-throughput screens (HTS) of 2,706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses and inspired HTS-enabled drug combination assessments encompassing 9,195 drug-drug assays. Top combinations were validated in vitro across patient-derived cell cultures representing the major DMG genotypes and in vivo across patient-derived xenograft models. The combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib emerged as a promising therapeutic combination. Transcriptional and metabolomics surveys demonstrated an NAD-dependent metabolic catastrophe driving the combination-induced cytotoxic response. These studies provide comprehensive single- and combination-agent drug screening data for DIPG and identify a candidate therapeutic strategy for clinical translation. We also explored the immune cell microenvironment of DIPG in comparison to adult glioblastoma (aGBM) using primary tumor tissue donations. Previous studies found that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, pediatric and adult glioblastoma are molecularly and genomically distinct, raising the question of whether they also have distinct interactions with the tumor immune microenvironment. We found that the leukocyte (CD45+) compartment in primary DIPG tissue is predominantly comprised of CD11b+ macrophages, while other cells (e.g. CD3 lymphocytes) can be found in aGBM. RNA sequencing of isolated tumor-associated macrophages revealed common gene programs related to extracellular matrix remodeling and angiogenesis, but demonstrated that DIPG-associated macrophages express fewer inflammatory factors. We also found that patient-derived DIPG cell cultures secrete fewer cytokines and chemokines than patient-derived aGBM cultures, and confirmed the low to absent expression of these factors in DIPG bulk and single-cell RNA sequencing data. These observations suggest an ineffective inflammatory response by DIPG-associated macrophages, which may be related to the low inflammatory signature of DIPG tumor cells. These findings also highlight that differences between DIPG and aGBM extend into their immune microenvironment, which carries implications for the development and application of immunotherapy-based treatments for DIPG
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lin, Grant Libing |
|---|---|
| Degree supervisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Palmer, Theo |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Grant L. Lin |
|---|---|
| Note | Submitted to the Neurosciences Program |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Grant Libing Lin
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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